Adipose Tissue and Adipokines in Health and Disease highlights emerging and important new research on the interrelationships of adipocytes with the immune system. The amount of information regarding the role of adipose tissue in health and disease continues to increase dramatically.
INTRODUCTION
The mass of the fat organ represents approximately 20% of body weight and is therefore one of the largest organs in the body. Each depot in the organ receives its own neurovascular pedicle, which is specific to subcutaneous depots and, in the case of visceral depots, usually depends on the pedicle associated with the associated organ.
GROSS ANATOMY
We recently described quantitative fat organ data of adult Sv129 mice maintained at different environmental temperatures (5). Most adipocytes are located in the adipose organ depots described above, but white adipocytes are also found in the skin, thymus, lymph nodes, bone marrow, parotid, parathyroid, pancreas, and other tissues.
LIGHT AND ELECTRON MICROSCOPY 1. White Adipose Tissue
VASCULAR SUPPLY
The expansion of the capillary network is quite different in the white and brown parts of the organ. In the brown areas, the density of the capillaries is much higher than in the white areas.
NERVE SUPPLY
During cold exposure, noradrenergic parenchyma fibers increase in the brown part of the organ (8). During fasting, noradrenergic parenchymal fibers increase in the white part of the organ (9).
HISTOPHYSIOLOGY
These two functions of the two tissues of the fat organ (WAT and BAT) are therefore balanced between them, because the intrinsic energy of lipids can be accumulated (WAT) or dissipated (BAT). The production of all these adipokines gave rise to the recent concept of the adipose organ as an endocrine organ (27,28).
DEVELOPMENT AND PLASTICITY
After exposure to cold, the increase in the number of brown adipocytes in white areas of the fat organ is accompanied by the appearance of brown adipocyte progenitors (41). Treatment with G3AR agonists causes development of brown adipocytes in white areas of the fat organ.
THE ADIPOSE ORGAN OF HUMANS
This appears to be due to a combination of increased lipoprotein lipase activity and decreased lipolytic activity in the gluteofemoral adipose tissue. In general, F2 adrenoreceptors are more abundant in human adipose tissue than in murine adipose tissue.
CONCLUSIONS
BAT has also been described as elevated in outdoor workers in Northern Europe (78) and in patients with pheochromocytoma (a noradrenaline-secreting tumor). Furthermore, rare cases of hibernoma-BAT tumors occurring in various anatomical locations, including subcutaneous and visceral fat, have been described (about 100 cases have been described in the literature [79] and we recently observed a case [Fig. 4] in which brown adipocytes expressed UCP1 and had the classic electron microscopy with typical mitochondria).
Metabolism of White Adipose Tissue
- TAG SYNTHESIS AND STORAGE
- F ATTY A CIDS F ROM C IRCULATING L IPIDS
- LIPOLYSIS AND RELEASE OF FATTY ACIDS
- CHOLESTEROL METABOLISM
- CONCLUSIONS
Its expression is also reduced in the adipose tissue of ob/ob and db/db mice ( 105 ). Perilipins are expressed in human adipose tissue and evidence has been provided for a role in the regulation of lipolysis in humans (129-131).
Leptin
- ADIPOCYTE BIOLOGY AND LEPTIN
- LEPTIN’S EFFECTS ON THE NEUROENDOCRINE AXIS
- LEPTIN RECEPTORS AND SIGNAL TRANSDUCTION IN THE BRAIN
- IMPLICATIONS OF LEPTIN SIGNAL TRANSDUCTION
- LEPTIN ACTION IN PERIPHERAL TISSUES
- CONCLUSIONS
The latter was supported by the localization of leptin receptors in the hypothalamus and several CNS nuclei related to nutrition and energy balance ( 15 ). Our and other studies have demonstrated profound trophic action of leptin in the brain of adult Lepob/obmice (83,84).
Adiponectin
- STRUCTURAL FEATURES OF ADIPONECTIN
- PLEIOTROPIC BIOLOGICAL FUNCTIONS OF ADIPONECTIN
- PUTATIVE ADIPONECTIN RECEPTORS
- CLINICAL STUDIES ON ADIPONECTIN 1. Plasma Adiponectin Levels and Adiposity
- ADIPONECTIN AS A POTENTIAL THERAPEUTIC TARGET
- CONCLUSIONS
In addition, the expression of adiponectin receptors was found to be decreased in obese individuals and type 2 diabetic patients (59,60). Whether the therapeutic effects of the PPAR agonists are mediated via induction of adiponectin remains to be investigated. The mechanism of adiponectin resistance, which has recently been reported in obese individuals (58,61), remains to be elucidated.
A DIPOKINES AS R EGULATORS
MMUNITY AND I NFLAMMATION
Vasoactive Factors and Inflammatory Mediators Produced in Adipose Tissue
- ADIPOSE TISSUE AS A DYNAMIC ENDOCRINE AND PARACRINE ORGAN
- ADIPOKINES WITH VASOACTIVE OR INFLAMMATORY EFFECTS IL-6 and TNF-F are among the well-known cytokines consistently found to be
- OTHER ADIPOSE-DERIVED FACTORS
- MOLECULAR LINKS UNDERLYING THE ADIPOSITY–
While adipsin expression has been shown to be reduced in mouse models of obesity, unchanged or increased levels have been reported in obese patients (39). However, only human adipose tissue has been shown to express CRP mRNA, which is negatively correlated with adiponectin expression in the same tissue (61). In obese patients, serum concentrations of the 164 amino acid isoform have been observed to depend on intra-abdominal fat accumulation (70).
Regulation of the Immune Response by Leptin
- LEPTIN MODULATION OF INNATE IMMUNITY
- LEPTIN MODULATION OF ADAPTIVE IMMUNE RESPONSE
- MECHANISMS OF LEPTIN ACTION IN IMMUNE CELLS
- LEPTIN AND PATHOPHYSIOLOGY OF THE IMMUNE SYSTEM It seems to be generally accepted that leptin may be an important signal that connects
In this context, tyrosine phosphorylation of the leptin receptor and activation of JAK-2 and STAT-3 by leptin stimulation was confirmed in a murine macrophage cell line (65). Newer data also point to a possible role of leptin in the pathophysiology of some autoimmune diseases. Therefore, investigating the role of leptin in the regulation of the immune response is still a challenge for the future.
Leptin in Autoimmune Diseases
- LEPTIN IN MULTIPLE SCLEROSIS
- LEPTIN IN TYPE 1 AUTOIMMUNE DIABETES
- LEPTIN IN RHEUMATOID ARTHRITIS
- LEPTIN IN LIVER AND KIDNEY IMMUNE-MEDIATED DISORDERS Protection of ob/ob mice from autoimmune damage is also observed in experimen-
- LEPTIN IN ENDOMETRIOSIS
- LEPTIN AND THE HYGIENE/AFFLUENCE HYPOTHESIS IN AUTOIMMUNITY
- CONCLUSIONS
Taken together, these data indicate an involvement of leptin in the pathogenesis of central nervous system autoimmunity in the EAE model. In addition, the authors suggested a local consumption of leptin in the joint, which may exert a protective effect against the destructive course of RA. These molecules, together with other angiogenic factors, are thought to be of fundamental importance in the pathogenesis of the disease.
Leptin and Gastrointestinal Inflammation
- LEPTIN AS PIVOTAL MEDIATOR OF INTESTINAL INFLAMMATION In several experimental colitis models, such as trinitrobenzene sulfonic acid (TNBS)
- DIRECT ROLE OF LEPTIN ON T-CELL ACTIVATION IN INTESTINAL INFLAMMATION
- BIOLOGICAL SIGNIFICANCE OF LEPTIN PRODUCED AT THE SITE OF INFLAMMATION
- INFLUENCE OF LEPTIN ON ANTIGEN PROCESSING AND PRESENTING CELLS
- SPONTANEOUS INTESTINAL INFLAMMATION
- INFECTIOUS COLITIS MODELS
- HUMAN INFLAMMATORY BOWEL DISEASE
- FUTURE PERSPECTIVE
- CONCLUSIONS
The in vitro data described in the introduction strongly suggested that leptin could in fact directly stimulate T cells as well as epithelial cells (14,25). Our own group demonstrated leptin production by LPMC as well as T cells from mesenteric lymph nodes in the CD4+CD45Rbhigh transfer model of colitis ( 37 ). Remarkably, in the absence of leptin or leptin signaling mice were partially protected against Clostridium toxin A-induced colitis.
Adiponectin and Inflammation
DISCOVERY OF ADIPONECTIN AND ITS CLINICAL SIGNIFICANCE When we started the comprehensive analysis of expressed genes in human adipose
The negative correlation between adiponectin levels and visceral fat is stronger than between adiponectin and subcutaneous fat concentration (Figure 1) (7). In a study of Pima Indians, individuals with high levels of adiponectin were less likely to develop type 2 diabetes than those with low levels (15). Plasma adiponectin levels are also reduced in people with hypertension, regardless of the presence of insulin resistance (19).
ADIPOSE TISSUE AND INFLAMMATION
Most importantly, plasma adiponectin concentrations are lower in people with coronary heart disease than in control subjects, even when BMI and age are matched. Kaplan-Meier analysis in Italian individuals with renal insufficiency showed that those with high adiponectin concentrations were free from cardiovascular death for longer than other groups (21). These results indicate that higher production of TNF-F in accumulated adipose tissue may be the cause of obesity-associated insulin resistance.
ADIPONECTIN AS A POTENT ANTI-INFLAMMATION ADIPOCYTOKINE
Our group detected adiponectin mRNA expression in human adipose tissue and demonstrated a significant inverse correlation between CRP and adiponectin mRNA (27). In addition, CRP mRNA levels in white adipose tissue of adiponectin KO mice were sli. The interrelationship of adiponectin and CRP levels in human plasma and adipose tissue may be involved in the development of atherosclerosis through inflammatory responses.
I NTERACTIONS B ETWEEN A DIPOCYTES
MMUNE C ELLS
Macrophages, Adipocytes, and Obesity
- OBESITY ACTIVATES INTRACELLULAR PATHWAYS THAT REGULATE INFLAMMATORY RESPONSES
- MACROPHAGE PHYSIOLOGY
- MACROPHAGES CONTRIBUTE TO OBESITY-INDUCED ADIPOSE TISSUE INFLAMMATION
- RECRUITMENT OF MONOCYTES TO ADIPOSE TISSUE IN OBESITY
In rodents, increased adipose tissue expression of inflammatory proteins has been mechanistically implicated in the development of important obesity-induced complications. Several lines of evidence have also implicated MCP—in particular, CCL2 (MCP-1) and CCL7 (MCP-3)—as participants in monocyte recruitment and chemotaxis to adipose tissue. Adipose tissue is an important site, possibly an initial site, in the development of obesity-induced inflammation.
Interactions of Adipose and Lymphoid Tissues
INTRODUCTION Signal Molecules
- B ONE M ARROW
Much of the confusion and paradoxical findings about the relationship between adipose stores and immune function can be clarified by taking into account site-specific properties of adipose tissue and its interactions with adjacent lymphoid cells. Nevertheless, the nodeless epididymal or perirenal depots remain the preferred choice of adipose tissue for cytokine studies (34,43,44). Local hypertrophy of adipose tissue associated with lymph nodes is not reversed within 3 months of termination of experimental inflammation (83).
PARACRINE INTERACTIONS OF ADIPOSE TISSUE IN HUMAN DISEASES
- L YMPHEDEMA
- HIV L IPODYSTROPHY
The structural fatty tissue in the eye orbit normally does not have visible lymphatic vessels, but these can develop if there is chronic inflammation (102). Similar interactions with HIV-infected lymphocytes could lead to the characteristic atrophy of facial adipose tissue. The abnormalities in the composition of adipose tissue and lymph node lymphoid cells in the mesentery of patients with celiac disease probably indicate similar deficiencies in the corresponding tissues elsewhere in the body.
CONCLUSIONS
Adipose Tissue and Mast Cells
ADIPOSE TISSUE
In humans, white adipose tissue (WAT), the main metabolic and excretory organ, is particularly well developed. Another major subtype of adipose tissue, brown adipose tissue, is present around the kidneys, adrenal glands, and aorta, as well as in the mediastinum and neck. Accordingly, the area of the role of adipose tissue in inflammation and metabolism has attracted considerable attention, illustrating the rapidly growing interest in understanding adipose tissue protein secretion.
ADIPOSE MAST CELLS
Immunohistochemical localization of NGF and its high-affinity receptor TrkA in newborn human subcutaneous skin adipose tissue. Currently, however, knowledge of the biology of mast cells in adipose tissue is limited compared to that of macrophages (13,19). Our ongoing study on the involvement of neurotrophins in adipose tissue biology also shows a prominent immunoreactivity for nerve growth factor (NGF) and its high-affinity receptor tyrosine kinase-A (Trk-A) expressed in the stromal compartment of subcutaneous adipose tissue ( Fig. 1 ).
PARACRINE EFFECTS OF ADIPOSE TISSUE
Epicardial adipose tissue is a visceral fat depot surrounding the heart, particularly the right ventricular free wall and left ventricular apex. There is compelling evidence indicating that both normal mammary gland development and breast cancer growth depend in part on the microenvironment, of which adipose tissue is a key component (ref. 28 and references therein). If this appears to be the case for adipose mast cells, it may further "inflame" adipose tissue.
Bone Marrow Adipose Tissue
- PLASTICITY OF BM ADIPOSE TISSUE 1. Evolution Throughout the Life Span
- MORPHOLOGICAL AND FUNCTIONAL CHARACTERIZATION OF BM ADIPOCYTES
- BM FAT CELL PRODUCTS
- BM ADIPOCYTES ORIGINATE FROM MESENCHYMAL STEM CELLS There are two stem cell compartments in mammal bone marrow. Besides the well-
- C OMMITMENT OF MSC S A MONG P HENOTYPES
- ADIPOCYTES AND BONE-FORMING CELLS
- BM ADIPOCYTES AND HEMATOPOIESIS
These results indicate that bone marrow adipocytes may contribute to the complex network of cytokines involved in the control of hematopoiesis and immune response. IL-6 may also be involved in the plasticity of the hematopoietic microenvironment, as BM-derived murine cell lines (LDA11 and MBA13.2), as well as murine (MC3T3) and human (MG-63) osteoblast-like cell lines, show IL the -6 receptor (80). Differences between the in vivo and in vitro situation or a different origin of the adipocytes in the different studies may contribute to these discrepancies.
